Database Query Results : Betulinic acid, , NF-kB

BetA, Betulinic acid: Click to Expand ⟱

Features:

Betulinic acid "buh-TOO-li-nik acid" is a natural compound with antiretroviral, anti malarial, anti-inflammatory and anticancer properties. It is found in the bark of several plants, such as white birch, ber tree and rosemary, and has a complex mode of action against tumor cells.
-Betulinic acid is a naturally occurring pentacyclic triterpenoid
-vitro concentrations range from 1–100 µM, in vivo studies in rodents have generally used doses from 10–100 mg/kg
Precursor: Betulin, via oxidation at C-28
Lipophilicity: High (poor aqueous solubility)
-half-life reports vary 3-5 hrs?. Reported half-life varies by formulation and species; several studies report multi-hour systemic persistence.
BioAv -hydrophobic molecule with relatively poor water solubility.

Main Cancer action
-Direct mitochondrial targeting in cancer cells
-Minimal effect on normal cells

Key pathways
-Mitochondrial membrane permeabilization
-ROS-mediated apoptosis
-Caspase-independent death

Chemo relevance: Generally compatible, Not a redox buffer

Pathways:
- often induce ROS production
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓
- Lowers AntiOxidant defense in Cancer Cells(Often associated with reduced redox buffering capacity in tumor cells (e.g., GSH depletion); NRF2 direction model-dependent.): NRF2↓, SOD↓, GSH↓
- May Raise AntiOxidant defense in Normal Cells: NRF2↑, SOD↑, GSH↑, Catalase↑ Reports suggest relative sparing of normal cells and preservation of antioxidant capacity in some models
- lowers Inflammation : NF-kB↓">NF-kB↓(typ), COX2↓, p38↓ (context-dependent; often stress-activated), Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : , MMPs↓, MMP2↓, MMP9↓, TIMP2, IGF-1↓, VEGF↓, ROCK1↓, FAK↓, NF-κB↓, TGF-β↓, α-SMA↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : P53↑, HSP↓(model-dependent), Sp proteins↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, CDK2↓, CDK4↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓, EMT↓, TOP1↓,
- inhibits glycolysis (secondary to mitochondrial stress) ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, HK2↓, ECAR↓, GRP78↑(ER stress), GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓,
- inhibits Cancer Stem Cells in some studies : CSC↓, GLi1↓, β-catenin↓, OCT4↓,
- Others: PI3K↓(typ), AKT↓(typ), JAK↓, STAT↓, β-catenin↓, AMPK↓(AMPK is often activated during metabolic stress), ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,
- Selectivity: Cancer Cells vs Normal Cells

Rank	Pathway / Axis	Cancer Cells	Normal Cells	TSF	Primary Effect	Notes / Interpretation
1	Intrinsic apoptosis (mitochondrial-mediated)	↑ mitochondria depolarization; ↑ cytochrome-c; ↑ caspase-9/3 activation	↔ limited activation (higher exposure required)	R, G	Execution of apoptosis	Betulinic acid (BA) is well known to engage the intrinsic apoptotic cascade, typically downstream of redox and signaling perturbations.
2	ROS / redox stress	↑ ROS (P→R)	↔ basal or antioxidant adaptation in some contexts	P, R	Stress induction	Many studies report ROS elevation in tumor cells exposed to BA; the direction and magnitude vary by cell type and exposure.
3	Mitochondrial permeability transition / ΔΨm loss	ΔΨm ↓ (R→G)	↔ maintained	R, G	Mitochondrial failure	Often observed as an early event preceding caspase activation in apoptosis studies.
4	PI3K / AKT / mTOR survival axis	↓ PI3K/AKT signaling; ↓ phospho-mTOR	↔	R, G	Survival/growth suppression	Betulinic acid often downregulates pro-survival kinase signaling, sensitizing cells to apoptosis and cytostasis.
5	NF-κB signaling	↓ NF-κB activity	↔	R, G	Pro-survival/inflammatory transcription suppression	Reduction in NF-κB activity limits pro-survival gene expression; supports sensitization to stressors.
6	MAPK re-wiring (JNK / ERK / p38)	Stress-MAPK shifts; JNK/p38 often ↑; ERK context-dependent	↔	P, R	Early stress signaling	MAPK responses vary by model, with stress-associated p38/JNK often activated and ERK modulation variable.
7	Cell-cycle checkpoints (p21, p27, cyclins)	↑ p21/p27; ↑ G1/S or G2/M arrest	↔	G	Proliferation arrest	BA often induces cell-cycle blockade, slowing proliferation before apoptosis commitment.
8	Angiogenic signaling (VEGF & related)	↓ VEGF; anti-angiogenic outputs	↔	G	Anti-angiogenic support	Typically seen at the level of reduced pro-angiogenic factor expression or secretion in longer-term assays.
9	EMT / invasion / migration programs (MMPs)	↓ MMP2/MMP9; ↓ migration/invasion	↔	G	Anti-invasive phenotype	Often measured as reduced invasive capacity and decreased expression of EMT markers in later time points.
10	Autophagy modulation	↑ LC3-II; ↑ autophagic flux (model dependent)	↔	G	Adaptive clearance / cell fate shift	BA can modulate autophagy, which may either sensitize cells to death pathways or reflect adaptive stress responses.

Time-Scale Flag (TSF): P / R / G

P: 0–30 min (primary/physical-chemical effects; rapid kinase/redox signaling)
R: 30 min–3 hr (acute redox and stress-response activation)
G: >3 hr (gene-regulatory adaptation and phenotypic outcomes)

NF-kB, Nuclear factor kappa B: Click to Expand ⟱

Source: HalifaxProj(inhibit)

Type:

NF-kB signaling
Nuclear factor kappa B (NF-κB) is a transcription factor that plays a crucial role in regulating immune response, inflammation, cell proliferation, and survival.
NF-κB is often found to be constitutively active in many types of cancer cells. This persistent activation can promote tumorigenesis by enhancing cell survival, proliferation, and metastasis.

Scientific Papers found: Click to Expand⟱

2755-

BetA,

Cytotoxic Potential of Betulinic Acid Fatty Esters and Their Liposomal Formulations: Targeting Breast, Colon, and Lung Cancer Cell Lines

in-vitro,

Colon,

HT29

in-vitro,

BC,

MCF-7

in-vitro,

Lung,

H460

eff↑, BA-Lip exerted stronger cytotoxic effects than the parent compound,
Casp3↑, BA’s fatty esters and their respective liposomal formulations facilitated apoptosis in cancer cells by inducing nuclear morphological changes and increasing caspase-3/-7 activity.
Casp7↑,
NF-kB↓, BA antiproliferative effects against U87MG and A172 glioblastoma cells revealing the downregulation of the NF-κB pathway and upregulation of caspase-3 and -9, thus suggesting that apoptosis occurred through mitochondria-mediated mechanisms

2743-

BetA,

Betulinic acid and the pharmacological effects of tumor suppression

Review,

Var,

ROS↓, BA improves the level of reactive oxygen species (ROS) production and alters the mitochondrial membrane potential gradient, followed by the release of cytochrome c (Cyt c), which causes the mitochondrial-mediated apoptosis of tumor cells via a caspas
MMP↓,
Cyt‑c↑,
Apoptosis↑,
TumCCA↑, BA can inhibit cancer cell growth and proliferation via cell cycle arrest
Sp1/3/4↓, BA, can inhibit the protein expression of Sp1, Sp2 and Sp4 through the microRNA (miR)-27a-ZBTB10-Sp1 axis
STAT3↓, BA can downregulate the activation of STAT3 through the upregulation of Src homology 2 domain-containing phosphatase 1 (SHP-1)
NF-kB↓, NF-κB can be inhibited by reducing the activation of inhibitor of NF-κB (IκBα) kinase (IKKβ) and phosphorylation of IκBα with BA
EMT↓, nvasion and metastasis of malignancies is prevented via epithelial-mesenchymal transition (EMT) and inhibition of topoisomerase I
TOP1↓,
MAPK↑, BA leads to the activation, via phosphorylation, of pro-apoptotic MAPK proteins, P38 and SAP/JNK, the formation of ROS and the upregulation of caspase
p38↑,
JNK↑,
Casp↑,
Bcl-2↓, BA downregulates Bcl-2 and upregulates the Bax gene in HeLa cell lines
BAX↑,
VEGF↓, BA can decrease the expression of VEGF via Sp proteins, thus having an antiangiogenic role
LAMs↓, BA suppresses the expression of lamin B1 in pancreatic cancer cells

2744-

BetA,

Betulin and betulinic acid: triterpenoids derivatives with a powerful biological potential

Review,

Var,

Apoptosis↓, Various studies have demonstrated that BE is able to induce apoptosis in numerous cancer cell lines (
TumCCA↑, 10 uM concentration, BE arrests cell cycle of murine melanoma B164A5 cells in S phase.
Casp9↑, BE is involved in the sequential activation of caspase-9, caspases 3 and 7, and cleaving of poly(ADP-ribose) polymerase (PARP) (Potze et al. 2014).
Casp3↑,
Casp7↑,
cl‑PARP↑,
MMP↓, mitochondrial membrane potential loss (Li et al. 2010; Potze et al. 2014).
ROS↑, increased reactive oxygen species (ROS) production
TOP1↓, BA was also shown to inhibit the proliferation of topoisomerases and therefore express anti-proliferative activity
NF-kB↓, BA was demonstrated to inhibit activating of NF-kB

2747-

BetA,

Betulinic acid, a natural compound with potent anticancer effects

Review,

Var,

selectivity↑, potently effective against a wide variety of cancer cells, also those derived from therapy-resistant and refractory tumors, whereas it has been found to be relatively nontoxic for healthy cells
Cyt‑c↑, induces Bax/Bak-independent cytochrome-c release.
*toxicity↓, In general, BetA is concluded to be less toxic to cells from healthy tissues.
TOP1↓, topoisomerase I/II
NF-kB↓, transcription factor NF-kB
ROS↑, Consistently, in glioma cells BetA-induced ROS generation
RadioS↑, Treatment with BetA in combination with irradiation resulted in additive growth inhibition of melanoma cells.
ChemoSen↑, BetA cooperated with anticancer drugs, doxorubicin and etoposide, to induce apoptosis and to inhibit clonogenic survival in SHEP neuroblastoma cells

2748-

BetA,

Betulinic Acid: Recent Advances in Chemical Modifications, Effective Delivery, and Molecular Mechanisms of a Promising Anticancer Therapy

Review,

Var,

Bcl-2↓, Cell death stimuli activate prodeath BCL-2 family proteins that in turn permeabilize mitochondrial outer membrane, thereby resulting in the release of Cyt C
MMP↓,
Cyt‑c↑,
Casp↑, Smac (second mitochondria-derived activator of caspase)/DIABLO (direct inhibitor of apoptosis [IAP] binding protein with low pI), and AIF (apoptosis-inducing factor) into the cytoplasm (27
Diablo↑,
AIF↑,
angioG↓, BetA's inhibition of growth-factor-induced angiogenesis seems at least partially owing to modulation of mitochondrial function in endothelial cells
BioAv↓, Current methods of conventional drug delivery using oral liquids or tablets are generally inefficient, with poor biodis- tribution, low solubility, long-term toxicity, and limited drug efficacy due to partial biodegradation, swelling, and ero- sion
NF-kB↓, BetA treatment inhibits the activation of NF-kB

2749-

BetA,

Anti-Inflammatory Activities of Betulinic Acid: A Review

Review,

Nor,

Inflam↓, betulinic acid as a promissory lead compound with anti-inflammatory activity
*NO↓, BA can inhibit the production of NO, mainly in macrophages cultures stimulated with bacterial lipopolysaccharide (LPS) and/or interferon gamma (IFN-ɣ)
*IL10↑, (BA) has a broad-spectrum anti-inflammatory activity, significantly increasing IL-10 production, decreasing ICAM-1, VCAM-1, and E-selectin expression and inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB),
*ICAM-1↓,
*VCAM-1↓,
*E-sel↓,
*NF-kB↓,
*IKKα↓, BA blocks the NF-κB signaling pathway by inhibiting IκB phosphorylation and d
*COX2↓, BA also inhibits cyclooxygenase-2 (COX-2) activity and, therefore, decrease prostaglandin E2 (PGE2) synthesis
*PGE2↓,
*IL1β↓, The production of critical pro-inflammatory cytokines, such as IL-1β, IL-6, IL-8, IL-12, and TNF, is also decreased by BA treatment
*IL6↓,
*IL8↓,
*IL12↓,
*TNF-α↑,
*HO-1↑, induction of HO-1 enzyme activity is associated with the anti-inflammatory effect of BA, since SnPP, an inhibitor of HO-1, promoted a partial reversal of BA’s effect on NF-κB activity,
*IL10↑, BA also increased the amount of IL-10, a well-known anti-inflammatory cytokine
*IL2↓, decreasing the production of pro-inflammatory cytokines, such as IL-2, IL-6, IL-17, and IFN-γ
*IL17↓,
*IFN-γ↓,
*SOD↑, BA decreased the production of the inflammatory mediators described above at the inflammation site and increased enzyme activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GRd) in the liver
*GPx↑,
*GSR↑,
*MDA↓, BA decreased malondialdehyde (MDA) levels, a key mediator of oxidative stress and widely used as a marker of free radical mediated lipid peroxidation injury, at the inflammation site
*MAPK↓, BA downregulates MAPK signaling pathways (ERK1/2, JNK, and p38) in the paw edema tissue, which, in part, explains the inhibition of cytokine production (IL-1β and TNF), COX-2 expression, and PGE2 production (Figure 3).

2752-

BetA,

Betulinic acid: a natural product with anticancer activity

Review,

Var,

selectivity↑, nontransformed cells of different origin, e.g., fibroblasts, melanocytes, neuronal cells and peripheral blood lymphocytes, have been reported to be much more resistant to the cytotoxic effect of BA than cancer cells
ChemoSen↑, BA was found to cooperate with various chemotherapeutic drugs, including doxorubicin, etoposide, cisplatin, taxol, and actinomycin D, to induce apoptosis and to inhibit clonogenic survival of tumor cells
RadioS↑, These reports suggest that using BetA as sensitizer in chemotherapy-, radiotherapy-, or TRAIL-based combination regimens may be a novel strategy to enhance the efficacy of anticancer therapy.
MMP↓, BA directly induces loss of mitochondrial membrane potenti
cl‑Casp3↑, BA, induced cleavage of both caspases-8 and -3 in cytosolic extracts.
Cyt‑c↑, cytochrome c, released from mitochondria undergoing BA-mediated permeability transition, activated caspase-3 but not caspase-8 in a cell-free system.
ROS↑, Cleavage of caspases-3 and -8 was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species (ROS).
NF-kB↑, BA is a potent activator of NF-kB in a variety of tumor cell lines.
TOP1↓, BA blocks the catalytic activity of topoisomerase I by abrogating the inter- action of the enzyme and the DNA substrate

2759-

BetA,

Chemopreventive and Chemotherapeutic Potential of Betulin and Betulinic Acid: Mechanistic Insights From In Vitro, In Vivo and Clinical Studies

Review,

Var,

chemoPv↑, chemopreventive and chemotherapeutic effects of betulin and betulinic acid by presenting in vitro, in vivo
ChemoSen↑,
*Inflam↓, right side depicts anti-inflammatory effect by suppressing proinflammatory mediators
*NRF2↑, boosting NRF2 (antioxidant/anti-inflammatory).
*NF-kB↓, suppressing proinflammatory mediators (NF-κB and COX)
*COX2↓,
ROS↑, By rapidly increasing the generation of reactive oxidative species and concurrently dissipating mitochondrial membrane potential in a dose- and time-dependent manner, betulinic acid also has an anticancer effect on melanoma cells
MMP↓,
Sp1/3/4↓, nude mice bearing LNCaP cell xenografts has been observed by betulinic acid treatment and this result was associated with reduction in the expression of Sp1, Sp3, and Sp4 proteins and vascular endothelial growth factor (VEGF)
VEGF↓,

2760-

BetA,

A Review on Preparation of Betulinic Acid and Its Biological Activities

Review,

Var,

Review,

Stroke,

AntiTum↑, BA is considered a future promising antitumor compound
Cyt‑c↑, BA stimulated mitochondria to release cytochrome c and Smac and cause further apoptosis reactions
Smad1↑,
Sepsis↓, Administration of 10 and 30 mg/kg of BA significantly improved survival against sepsis and attenuated lung injury.
NF-kB↓, BA inhibited nuclear factor-kappa B (NF-κB) expression in the lung and decreased levels of cytokine, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9)
ICAM-1↓,
MCP1↓,
MMP9↓,
COX2↓, In hPBMCs, BA suppressed cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PEG2) production by inhibiting extracellular regulated kinase (ERK) and Akt phosphorylation and thereby modulated the NF-κB signaling pathway
PGE2↓,
ERK↓,
p‑Akt↓,
*ROS↓, BA significantly decreased the mortality of mice against endotoxin shock and inhibited the production of PEG2 in two of the most susceptible organs, lungs and livers [80]. Moreover, BA reduced reactive oxygen species (ROS) formation
*LDH↓, and the release of lactate dehydrogenase
*hepatoP↑, hepatoprotective effect of BA from Tecomella undulata.
*SOD↑, Pretreatment of BA prevented the depletion of hepatic antioxidants superoxide dismutase (SOD) and catalase (CAT), reduced glutathione (GSH) and ascorbic acid (AA) and decreased the CCl4-induced LPO level
*Catalase↑,
*GSH↑,
*AST↓, A also attenuated the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) plasma level,
*ALAT↓,
*RenoP↑, BA also exhibits renal-protective effects. Renal fibrosis is an end-stage renal disease symptom that develops from chronic kidney disease (CKD).
*ROS↓, BA protected against this ischemia-reperfusion injury in a mice model by enhancing blood flow and reducing oxidative stress and nitrosative stress
*α-SMA↓, Moreover, BA reduced the expression of α-smooth muscle actin (α-SMA) and collagen-I

2727-

BetA,

Betulinic acid in the treatment of breast cancer: Application and mechanism progress

Review,

BC,

mt-ROS↑, Its mechanisms mainly include inducing mitochondrial oxidative stress, regulating specific protein (Sp) transcription factors, inhibiting breast cancer metastasis, inhibiting glucose metabolism and NF-κB pathway.
Sp1/3/4↓, By triggering the degradation of Sp1, Sp3, and Sp4, betulinic acid reduces the transcriptional activity of these factors
TumMeta↓,
GlucoseCon↓,
NF-kB↓,
ChemoSen↑, BA can also increase the sensitivity of breast cancer cells to other chemotherapy drugs such as paclitaxel and reduce its toxic side effects.
chemoP↑,
m-Apoptosis↑, variety of mechanisms, including inducing mitochondrial apoptosis, inhibiting topoisomerase
TOP1↓, betulinic acid may inhibit the ability of topoisomerase I or II to properly cleave and re-ligate DNA strands.

2716-

BetA,

Cellular and molecular mechanisms underlying the potential of betulinic acid in cancer prevention and treatment

Review,

Var,

AntiCan↑, BA has a range of well-documented pharmacological and biological effects, including antibacterial, immunomodulatory, diuretic, antiviral, antiparasitic, antidiabetic, and anticancer activities
TumCD↑, anticancer properties of BA are mediated by the activation of cell death and cell cycle arrest, production of reactive oxygen species, increased mitochondrial permeability, modulation of nuclear factor-κB and Bcl-2 family signaling
TumCCA↑,
ROS↑,
NF-kB↓,
Bcl-2↓,
Half-Life↝, The half-life eliminations were 11.8 and 11.5 h after 500 and 250 mg/kg of intraperitoneal (i.p.) BA administration
GLUT1↓, the expression of HIF target genes, such as GLUT1, VEGF, and PDK1 was also suppressed by BA
VEGF↓,
PDK1↓,

2717-

BetA,

Betulinic Acid Induces ROS-Dependent Apoptosis and S-Phase Arrest by Inhibiting the NF-κB Pathway in Human Multiple Myeloma

in-vitro,

Melanoma,

U266

10-40uM

in-vivo,

Melanoma,

Nude Mouse Xenograft Model

in-vitro,

Melanoma,

RPMI-8226

Apoptosis↑, BA mediated cytotoxicity in MM cells through apoptosis, S-phase arrest, mitochondrial membrane potential (MMP) collapse, and overwhelming reactive oxygen species (ROS) accumulation.
TumCCA↑, S-Phase Arrest in U266 Cells
MMP↓,
ROS↑, exhibited concentration-dependent increases in intracellular ROS
eff↓, ROS scavenger N-acetyl cysteine (NAC) effectively abated elevated ROS, the BA-induced apoptosis was partially reversed
NF-kB↓, BA resulted in marked inhibition of the aberrantly activated NF-κB pathway in MM
Cyt‑c↑, BA mediated the release of cyt c and activated cleaved caspase-3, caspase-8, and caspase-9 and cleaved PARP1
Casp3↑,
Casp8↑,
Casp9↑,
cl‑PARP1↑,
MDA↑, here is a concentration-dependent increase in MDA contents and reduction in SOD activities, especially for the high concentration group.
SOD↓,
SOD2↓, expression of genes SOD2, FHC, GCLM, and GSTM was all decreased following treatment with BA (40 μM)
GCLM↓,
GSTA1↓,
FTH1↓, FHC
GSTs↓, GSTM
TumVol↓, BA Inhibits the Growth of MM Xenograft Tumors In Vivo. BA-treated group were significantly reduced (inhibition ratio of approximately 72.1%).

2718-

BetA,

The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis

in-vitro,

AML,

U937

TumCCA↑, BA exerted a significant cytotoxic effect on U937 cells through blocking cell cycle arrest at the G2/M phase and inducing apoptosis, and that the intracellular reactive oxygen species (ROS) levels increased after treatment with BA.
Apoptosis↑,
i-ROS↑,
cycA1/CCNA1↓, down-regulation of cyclin A and cyclin B1, and up-regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 revealed the G2/M phase arrest mechanism of BA.
CycB/CCNB1↓,
P21↑,
Cyt‑c↑, BA induced the cytosolic release of cytochrome c by reducing the mitochondrial membrane potential with an increasing Bax/Bcl-2 expression ratio.
MMP↓,
Bax:Bcl2↑,
Casp9↑, BA also increased the activity of caspase-9 and -3, and subsequent degradation of the poly (ADP-ribose) polymerase.
Casp3↑,
PARP↓,
eff↓, However, quenching of ROS by N-acetyl-cysteine, an ROS scavenger, markedly abolished BA-induced G2/M arrest and apoptosis, indicating that the generation of ROS plays a key role in inhibiting the proliferation of U937 cells by BA treatment.
*antiOx↑, Accumulated evidence demonstrates that BA possesses various biological activities, including antioxidant, anti-inflammatory, hepatoprotective, and anti-tumor effects
*Inflam↓,
*hepatoP↑,
selectivity↑, BA are complex and depends on the type of cancer cells, without causing toxicity toward normal cells
NF-kB↓, Shen et al. (2019) recently reported that the suppression of the nuclear factor-kappa B pathway increased downstream oxidant effectors, thereby promoting the generation of reactive oxygen species (ROS) in BA-stimulated multiple myeloma cells.
*ROS↓, Although BA is known to have antioxidant activity that blocks the accumulation of ROS due to oxidative stress in normal cells (Cheng et al. 2019;

2722-

BetA,

Betulinic Acid for Cancer Treatment and Prevention

Review,

Var,

MMP↓, betulinic acid induced loss of mitochondrial membrane potential
Cyt‑c↑, betulinic acid was shown to trigger cytochrome c
cl‑Casp3↑, Cleavage of caspase-3 and -8 was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species.
cl‑Casp8↑,
ROS↑,
NF-kB↑, Betulinic acid was identified as a potent activator of NF-κB in a number of cancer cell lines
TOP1↓, betulinic acid was shown to inhibit the catalytic activity of topoisomerase I

2728-

BetA,

Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy

in-vitro,

Var,

NF-kB↑, BetA activates NF-kappaB in a variety of tumor cell lines.
IKKα↑, BetA-induced NF-kappaB activation involved increased IKK activity
eff↓, NF-kappaB inhibitors in combination with BetA would have no therapeutic benefit or could even be contraproductive in certain tumors, which has important implications for the design of BetA-based combination protocols.

2729-

BetA,

Betulinic acid in the treatment of tumour diseases: Application and research progress

Review,

Var,

ChemoSen↑, Betulinic acid can increase the sensitivity of cancer cells to other chemotherapy drugs
mt-ROS↑, BA has antitumour activity, and its mechanisms of action mainly include the induction of mitochondrial oxidative stress
STAT3↓, inhibition of signal transducer and activator of transcription 3 and nuclear factor-κB signalling pathways.
NF-kB↓,
selectivity↑, A main advantage of BA and its derivatives is that they are cytotoxic to different human tumour cells, while cytotoxicity is much lower in normal cells.
*toxicity↓, It can kill cancer cells but has no obvious effect on normal cells and is also nontoxic to other organs in xenograft mice at a dose of 500 mg/kg
eff↑, BA combined with chemotherapy drugs, such as platinum and mithramycin A, can induce apoptosis in tumour cells
GRP78/BiP↑, In animal xenograft tumour models, BA enhanced the expression of glucose-regulated protein 78 (GRP78)
MMP2↓, reduced the levels of matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, in lung metastatic lesions of breast cancer, indicating that BA can reduce the invasiveness of breast cancer in vivo and block epithelial mesenchymal transformation (EMT
P90RSK↓,
TumCI↓,
EMT↓,
MALAT1↓, MALAT1, a lncRNA, was downregulated in hepatocellular carcinoma (HCC) cells treated with BA in vivo,
Glycolysis↓, Suppressing aerobic glycolysis of cancer cells by GRP78/β-Catenin/c-Myc signalling pathways
AMPK↑, activating AMPK signaling pathway
Sp1/3/4↓, inhibiting Sp1. BA at 20 mg/kg/d, the tumour volume and weight were significantly reduced, and the expression levels of Sp1, Sp3, and Sp4 in tumour tissues were lower than those in control mouse tissues
Hif1a↓, Suppressing the hypoxia-induced accumulation of HIF-1α and expression of HIF target genes
angioG↓, PC3: Having anti-angiogenesis effect
NF-kB↑, LNCaP, DU145 — Inducing apoptosis and NF-κB pathway
NF-kB↓, U266 — Inhibiting NF-κB pathway.
MMP↓, BA produces ROS and reduces mitochondrial membrane potential; the mitochondrial permeability transition pore of the mitochondrial membrane plays an important role in apoptosis signal transduction.
Cyt‑c↑, Mitochondria release cytochrome C and increase the levels of Caspase-9 and Caspase-3, inducing cell apoptosis.
Casp9↑,
Casp3↑,
RadioS↑, BA could be a promising drug for increasing radiosensitization in oral squamous cell carcinoma radiotherapy.
PERK↑, BA treatment increased the activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptosis pathway and decreased the expression of Sp1.
CHOP↑,
*toxicity↓, BA at a concentration of 50 μg/ml did not inhibit the growth of normal peripheral blood lymphocytes, indicating that the toxicity of BA was at least 1000 times less than that of doxorubicin

2731-

BetA,

Betulinic Acid for Glioblastoma Treatment: Reality, Challenges and Perspectives

Review,

GBM,

Review,

Park,

Review,

AD,

BBB↑, Notably, its ability to cross the blood–brain barrier addresses a significant challenge in treating neurological pathologies.
*GSH↑, BA can also dramatically reduce catalepsy and stride length, while increasing the brain’s dopamine content, glutathione activity, and catalase activity in hemiparkinsonian rats
*Catalase↑,
*motorD↑,
*neuroP↑, in Alzheimer’s disease rat models, it can improve neurobehavioral impairments . BA has exhibited great neuroprotective properties.
*cognitive↑, BA improves cognitive ability and neurotransmitter levels, and protects from brain damage by lowering reactive oxygen species (ROS) levels
*ROS↓,
*antiOx↑, enhancing brain tissue’s antioxidant capacity, and preventing the release of inflammatory cytokines
*Inflam↓,
MMP↓, BA can decrease the mitochondrial outer membrane potential (MOMP)
STAT3↓, The compound can inhibit the signal transducer and activator of transcription (STAT) 3 signaling pathways, involved in differentiation, proliferation, apoptosis, metastasis formation, angiogenesis, and metabolism, and the NF-kB signaling pathway,
NF-kB↓,
Sp1/3/4↓, BA has shown an ability to control cancer growth through the modulation of Sp transcription factors, inhibit DNA topoisomerase
TOP1↓,
EMT↓, inhibit the epithelial-to-mesenchymal transition (EMT)
Hif1a↓, BA has also been associated with an antiangiogenic response under hypoxia conditions, through the STAT3/hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) signaling pathway
VEGF↓,
ChemoSen↑, BA has shown great potential as an adjuvant to therapy since its use combined with standard treatment of chemotherapy and irradiation can enhance their cytotoxic effect on cancer cells
RadioS↑,
BioAv↓, Despite having great potential as a therapeutic agent, it is hard for BA to fulfill the requirements for adequate water solubility, maintaining both significant cytotoxicity and selectivity for tumor cells.

2735-

BetA,

Betulinic acid as apoptosis activator: Molecular mechanisms, mathematical modeling and chemical modifications

Review,

Var,

mt-Apoptosis↑, BA and analogues (BAs) have been known to exhibit potential antitumor action via provoking the mitochondrial pathway of apoptosis
Casp↑, cytosolic caspase activation
p38↑, inhibition of pro-apoptotic p38, MAPK and SAP/JNK kinases [8],
MAPK↓,
JNK↓,
VEGF↓, decreased expression of pro-apoptotic proteins and vascular endothelial growth factor (VEGF)
AIF↑, BA was recognized to trigger the process of apoptosis in human metastatic melanoma cells (Me-45) by releasing apoptosis inducing factor (AIF) and cytochrome c (Cyt C) through mitochondrial membrane
Cyt‑c↑,
ROS↑, BA also stimulates the increased production of reactive oxygen species (ROS) that is considered a stress factor involved in initiating mitochondrial membrane permeabilization
Ca+2↑, Moreover, the calcium overload and thereby ATP depletion are other stress factors causing enhanced inner mitochondrial membrane permeability via nonspecific pores formation
ATP↓,
NF-kB↓, BA has also known to be involved in activation of nuclear factor kappa B (NF-ÎºB) that is responsible for apoptosis induction in variety of cancer cells
ATF3↓, According to Zhang et al. [14], BA stimulates apoptosis through the suppression of cyclic AMP-dependent transcription factor ATF-3 and NF-ÎºB pathways and downregulation of p53 gene.
TOP1↓, inhibition of topoisomerases
VEGF↓, ecreased expression of vascular endothelial growth (VEGF) and the anti-apoptotic protein surviving in LNCaP prostate cancer cells.
survivin↓,
Sp1/3/4↓, selective proteasome-dependent targeted degradation of transcription factors specificity proteins (Sp1, Sp3, and Sp4), which generally regulate VEGF and survivin expression and highly over-expressed in tumor conditions
MMP↓, perturbed mitochondrial membrane potential
ChemoSen↑, BA can support as sensitizer in combination therapy to enhance the anticancer effects with minimum side effects.
selectivity↑, Normal human fibroblasts [41], peripheral blood lymphoblasts [41], melanocytes [32] and astrocytes [30] were found to be resistant to BA in vitro
BioAv↓, The clinical use of BA is seriously challenging due to high hydrophobicity which subsequently causes poor bioavailability
BioAv↑, A BA-loaded oil-in-water nanoemulsion was developed using phospholipase-catalyzed modified phosphatidylcholine as emulsifier in an ultrasonicator [120].
BioAv↑, Aqueous solubility of BA may also be increased through grinding with hydrophilic polymers (polyethylene glycol, polyvinylpyrrolidone, arabinogalactan) [121,122].
BioAv↑, Subsequently, for further improvement in biocompatibility, a technique of nanotube coating was employed with four biopolymers i.e. polyethylene glycol (PEG), chitosan, tween 20 and tween 80.
BioAv↑, Similarly, BA-coated silver nanoparticles displayed an improved antiproliferative and antimigratory activity, particularly against melanoma cells (A375: murine melanoma cells)

2737-

BetA,

Multiple molecular targets in breast cancer therapy by betulinic acid

Review,

Var,

TumCP↓, Betulinic acid (BA), a pipeline anticancer drug, exerts anti-proliferative effects on breast cancer cells is mainly through inhibition of cyclin and topoisomerase expression, leading to cell cycle arrest.
Cyc↓,
TOP1↓,
TumCCA↑,
angioG↓, anti-angiogenesis effect by inhibiting the expression of transcription factor nuclear factor kappa B (NF-κB), specificity protein (Sp) transcription factors, and vascular endothelial growth factor (VEGF) signaling.
NF-kB↓, Inhibition of NF-kB signaling pathway
Sp1/3/4↓,
VEGF↓,
MMPs↓, inhibiting the expression of matrix metalloproteases
ChemoSen↑, Synergistically interactions of BA with other chemotherapeutics are also described in the literature.
eff↑, BA is highly lipid soluble [74,75], and it readily passes through membranes, including plasma and mitochondrial membranes. BA acts directly on mitochondria
MMP↓, decreases mitochondrial outer membrane potential (MOMP), leading to increased outer membrane permeability, generation of reactive oxygen species (ROS),
ROS↑,
Bcl-2↓, reducing expression of anti-apoptotic proteins Bcl-2, Bcl-XL and Mcl-1
Bcl-xL↓,
Mcl-1↓,
lipid-P↑, BA inhibits the growth of breast cancer cells via lipid peroxidation resulting from the generation of ROS
RadioS↑, The cytotoxicity effect of BA on glioblastoma cells is not strong; however, some studies indicate that the combination of BA and radiotherapy could represent an advancement in treatment of glioblastoma [
eff↑, BA and thymoquinone inhibit MDR and induce cell death in MCF-7 breast cancer cells by suppressing BCRP [

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 19

Pathway results for Effect on Cancer / Diseased Cells:

Infection & Microbiome ⓘ

Sepsis↓, 1,
Total Targets: 100

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

antiOx↑, 2, Catalase↑, 2, GPx↑, 1, GSH↑, 2, GSR↑, 1, HO-1↑, 1, MDA↓, 1, NRF2↑, 1, ROS↓, 4, SOD↑, 2,

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1, LDH↓, 1,

Cell Death ⓘ

MAPK↓, 1,

Migration ⓘ

E-sel↓, 1, VCAM-1↓, 1, α-SMA↓, 1,

Angiogenesis & Vasculature ⓘ

NO↓, 1,

Immune & Inflammatory Signaling ⓘ

COX2↓, 2, ICAM-1↓, 1, IFN-γ↓, 1, IKKα↓, 1, IL10↑, 2, IL12↓, 1, IL17↓, 1, IL1β↓, 1, IL2↓, 1, IL6↓, 1, IL8↓, 1, Inflam↓, 3, NF-kB↓, 2, PGE2↓, 1, TNF-α↑, 1,

Clinical Biomarkers ⓘ

ALAT↓, 1, AST↓, 1, IL6↓, 1, LDH↓, 1,

Functional Outcomes ⓘ

cognitive↑, 1, hepatoP↑, 2, motorD↑, 1, neuroP↑, 1, RenoP↑, 1, toxicity↓, 3,
Total Targets: 42

Scientific Paper Hit Count for: NF-kB, Nuclear factor kappa B

19 Betulinic acid

Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:42  Target#:214  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

Database Query Results : Betulinic acid, , NF-kB

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Metal & Cofactor Biology ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Kinase & Signal Transduction ⓘ

Protein Folding & ER Stress ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Functional Outcomes ⓘ

Infection & Microbiome ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Immune & Inflammatory Signaling ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

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